Facteurs acquis dans les glomérulonéphrites complément médiés

Background: The complement is an essential system part of innate immunity that can cause tissue damage and inflammation when it is dysregulated. Autoimmune abnormalities targeting the complement alternative pathway (AP) have been primarily involved in glomerular diseases, such as C3 glomerulopathy (C3G), primary Immunoglobulin-mediated membranoproliferative GN (Ig-MPGN), and post-infectious GN (PIGN). C3G and Ig-MPGN are chronic kidney diseases which have been commonly associated to autoantibodies that stabilize the AP C3 convertase (C3NeF). Moreover, monoclonal gammopathies (MG) may play a role in AP overactivation in adult patients with C3G. PIGN shares common disease features with C3G and Ig-MPGN at disease presentation but is associated to an overall excellent renal prognosis. In children, PIGN have been strongly associated to autoantibodies targeting the AP component Factor B (FB). Despite the high prevalence of immune factors targeting the AP in these glomerulopathies, their clinical significance remains controversial. Methods: In the study I, we evaluated the disease phenotype of patients with C3G (n=19) or primary Ig-MPGN (n=8), according to the functions of IgG autoantibodies on the AP C3 convertase (C3bBb) using novel Luminex assays. In the study II, 256 adult patients with a documented glomerular disease and complement exploration including anti-FB IgG screening were enrolled in the study. We evaluated the clinical relevance of anti-factor B antibodies and characterized their binding and functional properties in vitro. In the study III, the impact of MG on the disease profile and prognosis of adult patients with C3G (n=8) or primary Ig-MPGN (n=19) has been explored. Result: In the study I, 16 of 27 patients were identified with IgG autoantibodies increasing the C3bBb formation and/or stabilization. Nine patients (33%) carrying IgG autoantibodies exhibiting a dual function were associated with severe C3 consumption and poor kidney survival (P=0.02). In the study II, we identified 71 of 256 patients with anti-FB autoantibodies. we observed a strong association between anti-FB and infection-associated glomerulonephritis (IA-GN). Anti-FB titers were correlated with C3 consumption. The proconvertase C3bB formation and the C3bBb stabilization were highlighted as two important mechanisms of AP deregulation driven by anti-FB positive IgG. In the study III, we observed that MG-associated to C3G or primary Ig-MPGN is associated with a poor renal outcome and a chronic systemic overactivation of the complement classical pathway. Conclusion: The functional profile of IgG autoantibodies targeting C3bBb, and the diagnosis of MG revealed association with the severity of C3G and primary Ig-MGPN. Anti-FB autoantibodies are key drivers of AP dysregulation and are associated with the phenotype of IA-GN. This work provides crucial pieces in our understanding of the pathophysiology of AP-mediated glomerulopathies but also paves the way for the use of complement-targeted therapies to improve patient outcomes.